Movement disorders are a group of diseases that affect the ability to produce and control body movement, and are often associated with neurological disorders or conditions associated with neurological dysfunction. Movement disorders may manifest themselves in abnormal fluency or speed of movement, excessive or involuntary movement, or slowed or absent voluntary movement.
Movement disorders are frequently caused by impaired regulation of dopamine neurotransmission. Parkinson's disease (PD) is an example of a movement disorder associated with dysfunctional regulation of dopamine neurotransmission, which is caused by progressive degeneration of dopamine neurons. Tardive dyskinesia is another example of a movement disorder associated with dysfunctional regulation of dopamine neurotransmission.
In order to replace the lost dopamine, PD is currently treated with e.g. Levodopa (L-DOPA, a precursor of dopamine). Unfortunately, the treatment of PD with L-DOPA often gives rise to a specific type of dyskinesia called L-DOPA Induced Dyskinesia (LID) which is caused by excessive dopamine levels in the synapses.
Dopamine release and re-uptake is regulated by a number of neurotransmitters, including serotonin (5-HT). Serotonin acts by binding to a number of different serotonergic receptors, of which agonists and antagonists of some serotonergic receptors have been investigated for treatment of movement disorders.
Modulators of serotonin (5-HT) neurotransmission individually have been shown to ameliorate or prevent LID. One example thereof is sarizotan, which is a 5-HT1A agonist and a dopamine receptor antagonist (Grégoire et al: Parkinsonism Relat Disord. 2009; 15(6): 445-52). In a phase 2A study and in an open labeled study sarizotan reduced LID. However, in several large phase 2b studies no significant effects of sarizotan compared to placebo could be shown.
The effects of the 5-HT1A agonist buspirone on Parkinson's disease have been studied in a small open study (Ludwig et al: Clin Neuropharmacol. 1986; 9(4):373-8). It was found that doses (10-60 mg/day), which are normally used to treat patients suffering from anxiety, did not have any effects on Parkinson's disease or dyskinesia. At higher doses (100 mg/day) it was observed that buspirone reduced dyskinesia but with a significant worsening of disability ratings. This showed that high doses of buspirone could worsen the akinesia associated with Parkinson's disease.
Recently it has been shown that a combination of a 5-HT1A and of a 5-HT1B agonist increased efficacy in reducing LID in animal models (e.g. Muñoz et al: Brain. 2008; 131: 3380-94; Muñoz et al: Experimental Neurology 219 (2009) 298-307). The combined 5-HT1A and 5-HT1B agonist eltoprazine has also recently been suggested for treatment of LID (WO2009/156380). Eltoprazine is estimated to be equipotent in terms of activation of 5-HT1A and 5-HT1B receptors. The long term effects of the use of the compound for treatment are unknown.
5-HT1A agonists given in high doses can lead to the development of the serotonin syndrome or serotonin toxicity; a form of poisoning. Because of the severity of serotonin syndrome, it is therefore important to maintain a low exposure of the 5-HT1A agonist.
The present inventors have previously discovered that surprising synergistic effects arise from combining an agonist of two or more the 5-HT1B, 5-HT1D and 5-HT1F receptors, exemplified by zolmitriptan, with a 5-HT1A agonist, exemplified by buspirone, when assayed in an animal model for LID, thus effectively increasing the therapeutic index. While zolmitriptan generally fails to inhibit LID when administered alone, it proved effective in potentiating the effects of buspirone to inhibit LID—even at very low doses; i.e. doses of buspirone which alone failed to produce a significant effect on LID (WO2012/048710).
In PCT/DK2012/050190 (filed Jan. 6, 2012) and further provided herein, the present inventors have investigated administering zolmitriptan separately before administering buspirone and found additional beneficial effects by such sequential administration. In PCT/DK2012/050190 both compounds were administered by injections to achieve this further beneficial effect (s.c. or i.p.). However, repeated and timely separated injections are generally undesired especially for long-term treatments, and bolus injections may cause too-high plasma concentration doses which is a potential safety concern.